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Yoshihisa Ishiura, Shosaku Nomura, Yuka Ishii, Kai Imai, Yusuke Sawai, Takeshi Tamaki, Toshiki Shimizu, Naoyuki Miyashita, Tomoki Ito First Department of Internal Medicine, Kansai Medical University, Osaka, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiuray@takii.kmu.ac.jpAbstract: Cough, a frequent symptom encountered in clinical practice, often has a considerable impact on patients’ lives. There is an urgent need to investigate more potent antitussive treatments for chronic refractory cough, particularly atopic cough, which is a major cause of chronic refractory cough in Japan. Previous studies have shown that eosinophilic tracheobronchitis with hypersensitivity to sensory nerve C-fibers is the pathophysiology of atopic cough. Gefapixant is a first-in-class P2X3 antagonist that has recently become available for clinical use in patients with refractory coughs. A 64-year-old female non-smoker presented to our hospital with a complaint of chronic intractable cough due to atopic cough. Addition of gefapixant (90 mg/day) to her previous treatment improved her distressing cough, despite the partial efficacy of many other drugs. The findings of this case demonstrate that P2X3 inhibition is a viable therapeutic option for patients with chronic refractory cough caused by atopic cough. This case report offers valuable information regarding currently available treatment options for refractory chronic refractory cough caused by atopic cough. There remains an urgent need to clarify the disease entities presenting with chronic cough that can be effectively treated by inhibiting P2X3.Plain Language Summary: There is an urgent need to investigate more potent antitussive treatments for chronic refractory cough, because cough has a considerable impact on patients’ lives. Previous studies have shown that eosinophilic tracheobronchitis with hypersensitivity of sensory nerve C-fibers is the pathophysiology of atopic cough, which is a major cause of chronic cough in Japan. Gefapixant is a first-in-class P2X3 antagonist that has recently become available for clinical use in patients with refractory coughs. Herein, we present the case of a 64-year-old female with a refractory atopic cough. The gefapixant add-on improved her distressing cough, indicating that P2X3 inhibition could be a viable therapeutic option for patients with chronic refractory cough caused by atopic cough.Keywords: chronic cough, atopic cough, gefapixant, P2X3

Yoshihisa Ishiura,1 Masaki Fujimura,2 Noriyuki Ohkura,3 Johsuke Hara,3 Kahori Nakahama,1 Yusuke Sawai,1 Takeshi Tamaki,1 Ryuta Murai,1 Toshiki Shimizu,1 Naoyuki Miyashita,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; 2Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 3Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiura-@p2322.nsk.ne.jp; ishiuray@takii.kmu.ac.jpPurpose: The ‘treatable traits’ strategy for patients with chronic inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease (COPD), is a focus of interest, because it implements precision and personalized medicine. Asthma-COPD overlap (ACO), a phenotype involving both asthma and COPD, is an important disease entity because patients with ACO have significantly worse outcomes, conferring greater economical and social burdens. Some guidelines for ACO recommend add-on therapy of long-acting muscarinic antagonists to inhaled corticosteroids and long-acting β2 agonists. However, this approach is based on extrapolation from patients with asthma or COPD alone. Consequently, a ‘treatable traits’ approach suitable for ACO remains obscure.Methods: A 12-week open-label cross-over pilot study was conducted in patients with ACO to investigate the effect of tiotropium bromide (TIO) 5 μg/day add-on therapy to fluticasone propionate/formoterol fumarate (FP/FM) 500/20 μg/day compared with FP/FM 500/20 μg/day alone. A 4-week run-in period and two 4-week treatment periods were included.Results: A total of 18 male patients with stable ACO participated in this pilot study. All patients were ex-smokers. Mean values ± standard deviation (SD) for forced expiratory volume in 1 second (FEV1) were 1.21 ± 0.49 L after the run-in period, 1.20 ± 0.51 L after the FP/FM combination therapy period, and 1.30 ± 0.48 L after the TIO add-on therapy to FP/FM period. FEV1 values after the TIO add-on therapy FP/FM period were significantly higher than those after the run-in period (p < 0.01).Conclusion: TIO add-on therapy to FP/FM in patients with ACO, considered difficult to treat because of the presence of both asthma and COPD, resulted in improvements in lung function parameters in this real-world pilot study, indicating the potential value of TIO add-on therapy as a “treatable traits” option for standard treatment for ACO.Keywords: treatable trait, asthma-COPD overlap, tiotropium, fluticasone, formoterol, triple therapy

Nobuyasu Ishii, Toshiki Shimizu, Yoshihisa Ishiura, Hideki Amuro, Tohru Nishizawa, Takeshi Tamaki, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Moriguchi-City, Osaka, 570-8507, JapanCorrespondence: Toshiki ShimizuFirst Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-City, Osaka, 570-8507, JapanTel + 81-6-6992-1001Fax + 81-6-6992-1066Email shimizto@takii.kmu.ac.jpBackground: Tocilizumab (TCZ) is humanized monoclonal antibody against the interleukin-6 (IL-6) and receptor that has prominent efficacy for the treatment of rheumatoid arthritis (RA). We conducted a retrospective observational study to determine how long TCZ controls RA.Patients and Methods: We retrospectively reviewed the medical records of RA patients treated with TCZ. The aim of this study was to evaluate the contribution of clinical parameters to disease control time (DCT) in RA patients.Results: Overall, 144 patients were enrolled in the study. The median age of patients was 66 years (range: 34– 85 years). In univariate analysis, DCT was significantly increased in patients who had never received previous biologic disease-modifying anti-rheumatic drugs treatment (P = 0.0064). We also analyzed the contribution of the base line value of C-reactive protein (CRP) to DCT. We divided the patients with RA into two groups according to a cutoff value of 1.000 mg/dl. The median control times were 77.5 months (95% confidence interval [CI]: 44.8–not reached to median) and 34.5 months (95% CI: 17.0– 79.3) for patients with high and low CRP value, respectively. In univariate analysis, DCT was significantly increased in patients with a high CRP value (P = 0.0283). Multivariate analysis clearly revealed that a high baseline CRP value was an independent favorable predictive factor for longer DCT (hazard ratio, 0.608, 95% CI: 0.378– 0.981, P = 0.0416).Conclusion: These data clearly demonstrate that the baseline value of CRP was closely associated with long time DCT in patients of RA treated with TCZ.Keywords: rheumatoid arthritis, tocilizumab, C-reactive protein, platelet large cell ratio, disease control time

Yoshihisa Ishiura,1,2 Masaki Fujimura,3 Noriyuki Ohkura,4 Johsuke Hara,4 Kazuo Kasahara,4 Nobuyasu Ishii,1 Yusuke Sawai,1 Toshiki Shimizu,1 Takeshi Tamaki,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan; 2Respiratory Medicine, Toyama City Hospital, Toyama, Japan; 3Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 4Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa IshiuraFirst Department of Internal Medicine, Kansai Medical University, Kansai Medical University Medical Center, 10-15 Fumizono-Cho, Moriguchi, Osaka 570-8507, JapanTel +81-6-6992-1001Fax +81-6-6993-9837Email ishiura-@p2322.nsk.ne.jpPurpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone.Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 μg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 μg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization.Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55– 83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods.Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.Keywords: asthma-COPD overlap, budesonide, glycopyrrolate, formoterol fumarate, triple therapy

We report a case of ureteral transitional cell carcinoma (TCC) first recognized because of mechanical ileus due to intestinal metastasis without definitive evidence of hydronephrosis or ureteral mass on plain computed tomography. We believe this to be the first case of ureteral TCC that was first recognized because of mechanical ileus due to small intestinal metastasis. [ABSTRACT FROM AUTHOR]

The effects of residual carbon in precursors on phase formation of single Tl–O layer superconductors of TlBa2Can−1CunOy (n=3 and 4) have been investigated. The samples were prepared from Tl2O3 and precursors of Ba2Can−1CunO2n+1+δ(Cx) (n=3 and 4) with various residual carbon contents (x=0.02–0.19). Even a small amount of carbon promotes the formation of double Tl–O layer phases of Tl2Ba2Can−1CunOy (n=3 and 4). Using the carbon reduced precursor (x=0.02), a TlBa2Ca2Cu3Oy phase is synthesized directly in a silver-sheathed tape without such elements as Pb, Bi and Sr. [Copyright &y& Elsevier]